ROCK1 regulates insulin secretion from β-cells

Mol Metab. 2022 Dec:66:101625. doi: 10.1016/j.molmet.2022.101625. Epub 2022 Oct 29.


Objective: The endocrine pancreatic β-cells play a pivotal role in maintaining whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate β-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis.

Methods: Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1loxP/loxP, β-ROCK1-/-) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. An insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1-/- mice or β-cell lines with knockdown of ROCK1 was also evaluated. A proximity ligation assay was performed to determine the physical interactions between PK and ROCK1.

Results: Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1-/- mice displayed a progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium and ATP levels and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that glucose stimulation in β-cells greatly enhanced ROCK1 binding to PK.

Conclusions: Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and for glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

Keywords: Beta cells; Diabetes; Hyperglycemia; Insulin secretion; Pyruvate kinase; ROCK1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose / metabolism
  • Insulin Secretion* / physiology
  • Insulin* / metabolism
  • Mice
  • Pyruvate Kinase* / antagonists & inhibitors
  • Pyruvate Kinase* / metabolism
  • Pyruvates
  • rho-Associated Kinases*


  • Glucose
  • Insulin
  • Pyruvate Kinase
  • Pyruvates
  • Rock1 protein, mouse
  • rho-Associated Kinases